Called a silent killer, diabetes causes more deaths a year in America than AIDS. As USC researchers fight the disease on every front, USC doctors speed new techniques from bench to patient bedside.

ONE DAY YOUR DIET IS NOT AN ISSUE.You eat pretty much what you want, when you want. Then suddenly the good times come to an abrupt end. Every little bite has to be monitored. Sweets are pretty much forbidden, and carbohydrates must be carefully measured. Meals are scheduled at regular intervals, and the food on your plate is balanced in ways you previously only read about in magazines. Such is the startling  and difficult  transition that almost 800,000 Americans grapple with every year when they are diagnosed with diabetes. But the diagnosis represents much more than a set of irksome dietary restrictions. Called a silent killer, diabetes causes 200,000 deaths annually, more than AIDS. It is the most-diagnosed disease in the country, with more new cases than prostrate, breast, colon and lung cancers combined.And diabetes is on the rise: it afflicts 16 million Americans today, a six-fold increase over a few decades ago. The most common diabetes, called Type 2, used to strike primarily after age 45: now its showing up in teens and 20-year-olds.Its a horrendous public health crisis, says Richard Bergman, chairman of physiology and biophysics in the Keck School of Medicine of USC.

Above Left: Robert Ritzel, a post doc and research associate working in Peter Butlers lab at the Keck School of Medicine of USC. The lab, based in the Division of Endocrinology, is studying the hormone IAPP, which Butler believes may be responsible for Type 2 diabetes. Above: Richard Bergman

At USC, the sense of urgency has never been greater. Nor has the sense of hope. Last year the school unveiled its new USC Diabetes Research Center, capitalizing on more than two decades of research into both Type 1 diabetes (an autoimmune disease) and Type 2 diabetes (a metabolic disease). The start-up centers staff of 60 already includes 30 world-class investigators. At its first colloquium, held in April 2000, the center rolled out 18 presentations of major diabetes research now underway at USC.According to Bergman, the Keck School now ranks among the nations top diabetes research programs. Best of all, says the centers founding director with a smile, our people are relatively young. We have a strong future ahead of us.Bergman, who came to USC in 1980, is best known as the inventor of the minimal model  a computer-based metabolic test that accurately predicts who will and who wont develop diabetes. Considered a diagnostic standard, his approach has been adopted by labs throughout the world and used in some 400 independent studies.In 1988, the university recruited Thomas Buchanan, a professor of medicine, obstetrics and gynecology and a recognized world authority on pregnancy-related diabetes, or gestational diabetes mellitus (GDM). His research has revealed that of the women who develop this temporary condition, half will get Type 2 diabetes within five years. Buchanan pioneered a drug therapy that reduces this risk by 60 percent.Then in 1999 the Keck School brought aboard Peter Butler. USCs new chief of endocrinology and diabetes is an international authority on the function of pancreatic beta cells (the cells that produce insulin). Butler has shown in experiments that Type 2 diabetes is associated with build-up of a naturally occurring substance that produces sheets of plaque, which can kill beta cells. Butlers line of research may lead to new prevention or treatment strategies for diabetes  and may also shed light on a similar plaque build-up seen in Alzheimers disease.Driving the new centers position at the forefront of diabetes research is the Keck Schools forte in translational medicine  also known as the bench-to-bedside approach, which strives to speed advances made at the research bench to the patient bedside.Traditionally in medicine, theres sort of a firewall between lab and clinical sciences, explains Bergman. At USC, we have very good relationships between our basic scientists and clinical scientists  and thats rare.

KNOWN SINCE ANTIQUITY,diabetes mellitus derives from the Greek diabainein (to pass through) and from the Latin mellitus, (sweetened with honey). Before the discovery of insulin, diabetes patients didnt live long past the diseases onset. Untreated, the condition leads to ketosis, the accumulation of ketones (products of fat breakdown) in the blood. This is followed by acidosis (accumulation of acid in the blood), with nausea and vomiting. As the toxic products of disordered carbohydrate and fat metabolism continue to build up, the patient goes into diabetic coma, followed by death.
The prognosis improved vastly, however, in 1921 with Sir Frederick Bantings and Charles Bests extraction of the insulin hormone from the pancreas. Insulin shots meant doctors could prevent diabetic coma, though not the diseases disabling complications.This breakthrough produced an unfortunate side effect: once it was downgraded from death sentence to chronic condition, diabetes lost some of its menace. It was viewed as benign, says Butler. No one wrote a Love Story about it. In terms of research, it wasnt top of the list.

Modern public health statistics belie that innocuous image. Diabetes is now the sixth leading cause of death by disease in the United States. In two decades the death rate due to diabetes has increased by 30 percent, while death rates for other common illnesses, such as cardiovascular disease and stroke, have fallen. Diabetes is the leading cause of new blindness in adults, the leading cause of end-stage kidney disease, the leading cause of lower extremity amputations not related to injury and one of the major contributing factors to heart disease and stroke.Theres $100 billion a year spent on diabetes treatment or complications, Bergman says. Diabetes is responsible for most of the dialysis in this country. And, he warns, as people live longer, these costs will go up exponentially.Studies indicate that the number of diabetes patients doubles every 15 years. Currently the disease afflicts about 6 percent of the population, making it as common as asthma. Such statistics and trends have caught the attention of the U.S. Centers for Disease Control and Prevention, which recently labeled diabetes a serious public health problem.Congress authorized $837 million for diabetes research last year (compared to $442 million in 1999). Diabetes is finally catching up as a research priority.

IDENTIFICATION

KECK SCHOOL RESEARCHERS are guided by what Bergman calls the four pillars of diabetes investigation: identifying the at-risk population, preventing onset of the disease, treating those who have already developed the disease and finding a cure.The first line of attack is the search for people whom Bergman calls proto-diabetics  those who dont yet have the disease but are likely to develop it.
In the past, early identification wasnt an option. Usually those at risk werent recognized until symptoms began to appear, when it was already too late. Once diagnosed, diabetes is essentially irreversible. By then it has been developing for 15 years or more, says Bergman. Ideally we would catch people early and take measures to delay or prevent diabetes altogether.
Bergmans own research is responsible for a major breakthrough in such identification. The USC researcher spent 20 years developing his minimal model for measuring insulin resistance and pancreatic function.Drawing on his background in engineering, mathematical modeling and computer science, Bergman came up with a sophisticated computer model to assess the ever-fluctuating levels of insulin and sugar in the bloodstream. In a screening test, patients are injected with glucose and a pancreas-stimulating compound, and then are monitored over several hours. Based on timed lab results, Bergman can rank an individuals diabetes risk from lowest to highest on a disposition index. Though it is costly and time-consuming, the minimal model became the standard for predicting Type 2 diabetes. Bergman has since developed a simplified, less invasive version now in broad use.As Buchanan showed first, thanks to drugs that enhance a patients insulin-sensitivity doctors are now able to delay the onset of the disease in those who come up proto-diabetic on Bergmans test. This approach opens the possibility of real preventive treatment, which pharmaceutical companies are exploring.
Easier to identify are women with gestational diabetes. Obstetricians routinely test for glucose intolerance during regular prenatal visits because, left untreated, the condition can lead to serious pregnancy complications. After delivery blood sugar levels usually return to normal. However, more than half the women diagnosed with gestational diabetes will develop Type 2 diabetes within five years, according to studies by Buchanan and his USC colleagues.
These are women who have weak beta cells, says Buchanan, If the cells have to work hard, like in pregnancy, they appear to wear out faster than other peoples cells.
To determine whether the onset of Type 2 diabetes could be prevented, Buchanan and his team gave women with gestational diabetes an antihyperglycemic drug after delivery to keep the beta cells from failing. Three to five years of this therapy changed the insulin resistance of cells and reduced the load on the pancreas.We were able to cut the incidence of Type 2 diabetes among women with gestational diabetes by 60 percent, says Buchanan, who heads the General Clinical Research Center at Los Angeles County+ USC Medical Center.
Buchanan and his team are testing new antihyperglycemic agents while continuing to follow past patients to see if the rate of Type 2 diabetes remains low. Buchanan is expanding his research to determine if siblings of those with gestational diabetes are at higher risk.
Genetics research is another important frontier for identifying those at risk. Although risk factors include obesity and inadequate exercise, diabetes is not simply the result of an inactive lifestyle. Genetic markers for both Type 1 and Type 2 diabetes have already been identified.
Today diabetes is viewed as a combination of genetics that evolved over thousands of years when not much food was available, and a relatively new environment where theres a lot of food and not much physical activity, Buchanan says.Researchers now believe theres no single diabetes gene, but rather a number of them  including at least three on chromosome 20 that work in concert to set the stage for diabetes.
This has been a very frustrating avenue, because if there are too many markers, genetics may not be useful for identification purposes, says Bergman, who is part of a massive international effort to decipher the diseases genetic code by studying 1,200 Finnish families.
On the other hand, Buchanan says, genetics research has revealed new mechanisms that were not previously thought to have anything to do with blood sugar metabolism. These could lead to new interventions.

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Theres $100 billion a year spent on diabetes treatment or complications. Diabetes is respon-sible for most of the dialysis in this country. And as people live longer, these costs will go up exponentially.

In the old days, the children identified with diabetes would normally be Type 1. Now were seeing Type 2 diabetes diagnosed much earlier in life than ever before, among teens and people in their 20s.